Acyl derivatives of aminonaphthalene-sulfonamide



United States Patent vACYL DERIVATIVES OF AMIN ON APHTHALENE-SULFONAMIDE Takeo Ueda, Tokyo, Sadatake Kato, Osaka-tn, ShigeshiToyoshima,.0saka, and Tsuneo Wachi, Tokyo, Japan, assignors toDainippon. Pharmaceutical Co., Ltd., I-Iigashi-ku, Osaka, Japan NoDrawing. Original application June 1 7, 1954, Ser. No. 437,582. Dividedand this application Apr. 5, 1957, Ser. No. 650,830

Glaims priority, application Japan Sept. 17, 1953 6 Claims. 01. 260-401)This invention relates to acyl derivatives of aminonaphthalenesulfonamide.

A few aminonaphthalenesulfonamide derivatives were reported on to someextent in E. H. Northeys work The Sulfonamides and Allied Compounds(1948), these compounds (I) being prepared, like most sulfanilamides, bycondensing acetaminonaphthalenesulfonylchloride (H) with an aminocompound (III) to produce substituted acetaminonaphthalenesulfonamide(IV) and hydrolyzing the latter. Upon examination of these compoundswith respect to their anti-biotic property, there was little orsubstantially no eifectivenessfi Therefore, it was reported that thecompounds of this series were unpromising for use as antimicrobialdrugs.

The proposed compounds were designated by the following formula whereR"i-'s""o'i 1"e of several organie'radicals other "than acyl, eigiaphenyl' group.

According to the present invention, new a cyl derivatives (V) ofaminonaphthalenesulfonamide have. been synthesized, which have not beenreported by Northey or by any others. These new compounds showremarkable antiviral property and are useful as antiviral drugs.

The general formula of these compounds is NHCOIVQ SOaNHCOR (V) :where Ris a lower alkyl radical (i.e. 0 -0, and R is a higher alkyl'radical-(i.e. C r-C and the NHCOR and uct is recrystallized from--asuitableorganic solvent to action rate is higher.

'SO NHCOR maybe either on one and the same benzenoid nucleus of thenaphthalene skeleton or on difierent nuclei thereof.

The compounds of this series may most conveniently be prepared bycondensing a sulfonarnide compound (VI) with an acyl halide (VII) or anacylation agent such as an acid anhydride. The method is illustrated bythe following chemical equation:

NHCOR' NHCOR RCOX Boone somn. solNno 0 R (V1) (VII) (V) where R and R'are as defined above, and X is halogen. Alternatively, one may startwith aminonaphthalenesulfonamide: v 7

NH, v A NHCOR j soiNm SOzNHCOR The acyl-aminonaphthalenesulfonacylamide(VIII) is then hydrolyzed, aminosulfonacylamide (X) being obtained asfollows:

Nncon NH:

'somnooa soiNrroon The hydrolysis may be afliected in a medium such aswater or an organic solvent in the presence of an acid or base withheating. a

The aminosulfonacylamide (X) may be converted int the desiredacylaminonaphthalenesultonacylamide as fol-, lows: I

NH: NHCOR solNnoo ii so Nncon" In any of these condensation reactions,water and organic solvents as well as aqueous organic solvents areemployed as medium, and basic substances are added as neutralizingagents to promote the reactions. Among such neutralizing agents;pyridine and acetone give most favorable results, in general. Thereaction temperature rna'ybe ambient but, in general, is preferably atthe boiling point of the employed solvents, in which case the re- Theresultant acyl substituted aminonaphthalenesulfonamide is isolated fromthe reaction mixture byaddition of an acid thereto, from which the addedsolvent isthen distilled off. The isolated prodobtain the finishedproduct, which may h e-neutralized with an alkaline substance to obtainwater soluble alkaline material.

Alternatively, an acylation agent may be reacted withnitronaphthalenesulfonamide (XI) to producenitronaphthalenesulfonacylamide-(XII), which in turn is. reducedPatented Aug. 16

, 3 to obtain the aminonaphthalenesulfonacylamide (X), thus The firstreaction may be achieved in manner similar to that in the aforementionedcondensation reaction, while the second reaction maybe achievedaccording to the conventional manner of reducing aromatic nitrocompounds. 1 p The aminonaphthalenesulfonacylamide may also be preparedby reacting aminonaphthalenesulfonylchloride (XIII) with an amidine(XIV), and then heating the same with an acid, thus a NH:

HaN

//C'' HN S 011 SOaNH-C-R (XIV) somn-fi-R soa Ho-onAminonaphthalenesulfonacylamide may also be obtained by reactingnitronaphthalenesulfonylchloride (XV) wit-h amidine and heating the samewith an acid to produce nitronaphthalenesulfonacylamide (XVI) which inturn is reduced by a normal process, thus 1 Compound (X) may beconverted intocompound (V) according to reaction (A) supra.

The acyl derivatives of aminonaphthalenesulfonamide represented byFormula V are in general colorless crystalline substances and welldefined compounds. They are soluble in organic solvents and also solublein aqueous alkali, forming alkali salts. Increase in the number ofcarbon atoms in the acyl groups results in a decrease in the solubilityin water of the alkali salts. v I

These acyl derivatives of FormulaV have been found to have antiviralproperty. The in vitro elfect of the compounds may be illustrated asfollows:

Test process: mixtures of infectivebrain suspension in concentration of10" of Encephalites'japonica, the Nakayama strain (LD corresponding to10- are prepared in 0.1-0.01% solution of the compound, and injectedintracerebrally at 22 C. into groups of mice one hour after the mixingof the virus and the compound solution. Results are given in thefollowing tables by survival ratios.

TABLE A In vitro effect of M-acyl-4-acetaminonaphthalenesulfonamide N HOO CH:

[Employed virus: The Nakayams strain of the Japanese encephalitisviruses; virus concentration: Illmedical solution concentrationOBS-0.01%; contact time: 1 hour (at 22 C.).]

Aeyl (00R) groups of the compounds 0.05% 0.025% 0.01%

CO.CHa 0 0 0 -COCH2.CH: 0 0 0 -CO (01 1202033...- 0 0 0 -CO (CH2) ACHs 00 0 --CO(CH2) eCHa 5/10 0 0 CO(CH2) sCHa 9/9 0 0 CO(GH;)10CH3-. 9/9 7/102/10 CO(CH2)nGHs 9/9 9/9 5/10 CO (CH GHs-.- 9/10 7/8 5/10 -CO(CH2)10CH9/10 10/10 9/9 CO(CH2) sCH-G 7/7 0 0 CO(CH:)7CH=C 7/10 5/10 0 COCnH5 0 00 C OCHgCaH5 0 0 0 CO CH=OHCuHs 0 0 0 Control 0/10 TABLE B I n vitroeffect of N -dodecanoyll-acylmmnonaphthalenesulfonamlde IITHC O R SOgNHCO (CHahcOHs N -acyl (COR) group of the 0.05% 0.025% 0 01% K eompoun sCOCH:CH: 8/10 3/10 --OO (GHghOHs-.. 10/10 3/10 -60 (OH2)4OHB 9/10 5/10-CO (CH7)eCHs.- 7/10 0/10 ClO(CH2) sCHa" 10/10 3/10 (CHa)1oC 9/ 0/ CO(CH2)12CH3 3/10 0/10 -OO(GH2)uUHa... 0 10/10 -UO(CH2)10C a 1/10 1/10 CO(CHa)sCH=CHa 5/9 3/11 The virus dilutions in concentration of 10- ofpoliomyelitis virus, the Lansing strain (LD corresponding to 10- wereprepared in 0.30.01% solutions of the compounds, aud injectedintracerebrally into groups of mice 5 at 22 C. one hour after the mixingof the virus and the compounds. Results are given in the followingtable.

TABLE C In vitro effect of N -acyl-4-acetaminonaphthalenesulfonamideITIHCOCH:

BO1NHCOR Acyl (COR) groups of the compounds -COCH3 O COCHzCHz-CO(CHz)zOHs.. 0 H CH3 0 -CO(CH2)1CH=CH(C 6/9 0 005135 0 -COCH2C&H5 0--COCH=CHC5H5 3/6 Contr 0/10 EXAMPLE 1 p N -dodecanoyl 4acerylaminonqphthalenesulfonamide Employing 5 parts of4-acetylaminonaphthalenesulfonamide, about half thereof were suspendedin 10 parts by volume of dry pyridine. The mixture was kept at 80-90,and about one third of 4 parts of dodecanoyl chloride was graduallystirred thereinto. The remaining portion of the amide was then added tothe mixture, and the remaining portion of the chloride was stirredthereinto dropwise, care being taken to maintain the temperature at notabove 110 C. The reaction mixture was kept at 100-110 for minutes tocomplete the reaction. The reaction mixture was poured into a mixedsolution of 100 parts by volume of water and 11. parts by volume ofconcentrated hydrochloric acid, and theprecipitate was recovered byfiltration. The precipitate was dissolved in about 200 parts by volumeof warm water, the pH adjusted to 9 with caustic soda, and filtered. Thefiltrate was acidified with acetic acid for reprecipitation. Theresulting precipitate was crudeN-dodecanoyl-4-acetylaminonaphthalenesulfonamide with melting point of182 The yield was 6.5 parts, a portion of which was recrystallized =from80% alcohol.

Melting point: ZOO-201.

Colorless, minute and plate-like crystals.

Analysis: Calculated for C24H3404NQS N, 6.28 "Found:

Temperatures are a 8 EXAMPLE 2 N -tetradecanoyl4-acetylaminonaphthalenesulfanamide About half of 3.2 parts of4-acetylaminonaphthalenesulfonamide was suspended in 8 parts by volumeof dry pyridine, and kept at 80-90, about one third of 2.7 parts oftetradecanoyl chloride being gradually stirred into the reactionmixture. The remaining amide was then added, and the remaining chlorideadded dropwise, carefully maintaining the temperature at not exceeding110. The stirring was continued for 15 minutes at 100-110 to completethe reaction. The reaction mixture was then poured into a mixed solutionof about 100 parts by volume of water and 8 parts by volume ofconcentrated hydrochloric acid to separate the precipitate. Theprecipitate was recovered by filtration, and dissolved in about 150parts by volume of warm water. The pH of the solution was adjusted to 9with caustic soda, and the solution filtered. The filtrate was acidifiedwith acetic acid and the product reprecipitated. The recoveredprecipitate was crude N-tetradecanoyl-4-acetylaminonaphthalenesulfonamide. The yield was 5parts, a portion of which was recrystallized from 80% alcohol.

Melting point: 152-1565". White and plate-like crystals. Analysis:Calculated for C H O N S: N, 5.94. Found:

EXAMPLE 3 N -hexaaiecanoyl 4-acetylaminonaphthalenesulfonamide Abouthalf of 6 parts of 4-acetylaminonaphthalenesulfonamide was suspended in12 parts by volume of dry pyridine, and kept at 80-90". About one thirdof 5.5 parts of hexadecanoyl chloride was gradually stirred into thereaction mixture. The remaining amide was then added, and the remainingchloride was stirred thereinto, carefully keeping the temperature at notexceeding 110. The stirring was continued for 15 minutes at 100-110 tocomplete the reaction. The reaction mixture was poured into a mixture ofabout 100 parts by volume of water and 12. parts by volume ofconcentrated hydrochloric acid to separate a precipitate. Afterfiltration, the residue was dissolved in about 150 parts by volume ofwarm water, pH being adjusted to 9 with caustic soda. After filtration,the filtrate was acidified with aceticacid, and the .resultantprecipitate was recovered by filtration. There was obtained crude N-hexadecanoyl- 4-acetylaminonaphthalenesulfonamide having a meltingAnalysis: Calculated for C H O N S:

point of 151-158. The yield was 7 parts, a portion of which wasrecrystallized from 80% alcohol.

Melting point: 169-1705. White and plate-like crystals.

N, 5.58. Found: N, 5.72.

EXAMPLE 4 N -octadecanoyl 4-acetylaminonaphthdlenesulfonamide a waterand 10 parts by volume of concentrated hydrochloric acid, the separatedprecipitate being recovered by filtration. The precipitate was dissolvedin about parts by volume of warm water, the pHbeing adjusted to 9 withcaustic soda, and filtered. The filtrate was acidified with acetic acid,and they resultant precipitate was recovered by filtration. Crude N-octadecanoy1-4-,

acetylaminonaphthalenesulfonamide having a melting point of 162-165 wasobtained. The yield was 8 parts, a portion of which was recrystallizedfrom 80% alcohol.

N -undecylenyl-4-acetylaminonaphthalenesulfonamide About half of 6 partsof 4-acetylaminonaphthalenesulfonamide was suspended in 10 parts byvolume of dry pyridine and the temperature was kept at 70-80. About onethird of 4 parts of undecylenyl chloride was gradually stirred into thereaction mixture. The reaction mixture was then maintained at 100-105,the remaining amide was added thereto, and then the remaining chloridewas stirred thereinto, carefully maintaining the temperature at notexceeding 110. The stirring was continued for 20 minutes to complete thereaction. The reaction mixture was then poured into a mixture of about50 parts by volume of Water and 12 parts by volume of concentratedhydrochloric acid, the separated precipitate being recovered byfiltration. The precipitate was dissolved in about 300 parts by volumeof warm water, the pH adjusted to 9 with caustic soda, and filtered. Thefiltrate was acidified with acetic acid to efiect reprecipitation. Theprecipitate was recovered by filtration to obtain crude N-undecylenyl-4-acetylaminonaphthalene-sulfonamide having a melting pointof l64168. The yield was 7.5 parts, a portion of which wasrecrystallized from 70% alcohol.

Melting point: 167-173". Colorless, rhombus and plate-like crystals.Analysis: Calculated for C H O N S: N, 6.52. Found:

EXAMPLE 6 N -leyl-4-acetylaminonaphthalenesulfonamide About half of 6parts of 4-acetylaminonaphthalenesulfonamide was suspended in 12 partsby volume of dry pyridine, and the temperature was maintained at 70-80".About one third of 6 parts of 9-octadecanoyl chloride was graduallystirred into the reaction mixture. The reaction mixture was thenmaintained at a temperature of 100-105 the remaining amide was addedthereto and then the remaining chloride was stirred thereinto, carefullymaintaining the temperature at not exceeding 110. The stirring wascontinued for 20 minutes at 105-110, to complete the reaction. Thereaction mixture was poured into a mixed solution of about 50 parts byvolume of water and 12 parts by volume of concentrated hydrochloricacid, and the separated precipitate was recovered by filtration. Theprecipitate was then dissolved in about 300 parts by volume of warmwater, the pH being adjusted to 9 with caustic soda, and filtered. Thefiltrate was acidified with acetic acid and reprecipitated. The crude N-01eyl-4-acetylaminonaphthalenesulfonamide obtained had a melting pointof 149-153". The yield was 8.5 parts, a portion of which wasrecrystallized from 85% alcohol.

Melting point: 159.5-161". White and powdery crystals. Analysis:Calculated for C H 0 N S: N, 5.30. Found:

EXAMPLE 7 N -d0decan0yl-N -pr0pi0nyl-4-aminonapthalenesulfonamide 1.4parts of 4-propionylaminonaphthalenesulfonamide were suspended in 6parts by volume of pyridine, and kept at 90-l00 with stirring. 1.1 partsof dodecanoyl chloride were gradually poured into the reaction mix-ture.

The stirring-was continued for 15 minutes at 100-110 to complete thereaction. The reaction mixture, after cooling, was poured into a mixtureof 30 parts by volume of water and 6 parts by volume of concentratedhydrochloric acid to separate the precipitate which was collected byfiltration to obtain a crude product N -dodecanoy1-Npropionyl-4-aminonaphthalenesulfonamide. The crude product wasrecrystallized twice from 70% alcohol.

Melting point: 1525-1545". Small plate-like crystals, soluble in causticalkali solution. Yield: 1.3 parts. Readily soluble in hot alcohol.Analysis: Calculated for C H O N S: N, 6.09. Found:

EXAMPLE 8 N -0ctan0yl-5-acetylaminonaphthalenesulfonamide 0.3 part of N-octanoyl-5-aminonaphthalenesulfonamide was added to 1 pant by volume ofacetic anhydride, and

after keeping at a temperature of 50-60 for 15 minutes,

the mixture was cooled down. To this reaction mixture was added a smallquantity of toluene, and the separated precipitate was collected byfiltration. The collected precipitate-N octanoyl 5acetylaminonaphthalenesulfonamide-was then recrystallized twice from 90%alcohol.

Melting point: 220-223. Colorless, needle-like crystals. Yield: 0.18part. AnIaTlysis: Calculated for c H o.,N s:'N, 7.18. Found:

EXAMPLE 9 N -d0decanoyl-5-acetylaminonaphthalenesulfonamide 0.8 part ofN -dodecanoyl-5-aminonaphthalenesulfonamide was added to 3 parts byvolume of acetic anhydride, and after heating to 50-60 for 15 minutes,the mixture was cooled down. A small amount of toluene was then added tothe reaction mixture, and the separated precipitate was collected byfiltration. The collected precipitate-N dodecanoyl 5acetylaminonaphthagnegullfonamide-wvas recrystallized twice from co 0Melting point: 183-184". Colorless and flaky crystals. Yield: 0.6 part.Analysis: Calculated for C H O N S: N, 6.28. Found:

EXAMPLE 10 N dodecanoyl-8-z2cetyla'minonaph1thalenesztlforwlmide Meltingpoint: 157-158.

Light yellowish plate-like crystals.

Analysis: Calculated for C H O N S:

Found: N, 6.51%.

' 2.2 parts of the so-obtained N-dodecanoyl-8-nitronap'hthalenesulfonamide were dissolved in 50 parts byvolume of alcohol. To this solution was added palladium-carbon preparedfrom 5 parts by volume of 15% PdCl and 0.5 part of active carbon tosubject the solution to catalytic reduction. After the calculated amountof hydrogen had been absorbed, the reaction mixture was filtered.Alcohol was distilled off from the filtrate,

mam

Melting point: 129.

Yellowish flaky crystals.

Analysis: Calculated for C H O N S: N, 6.92%.

Found: N, 6.89%.

0.5 part of N -dodecanoyl-8-aminonaphthalenesulfonamide-(Z) was added to2 parts by volume of acetic anhydride. The mixture was boiled for 30minutes on an oil bath, and then poured into ice water. The separatedsolids were filtered out. The solid material was recrystallized from 70%alcohol, and 0.3 part of the final product, N-dodecanoyl-8-acetylaminonaphthalenesulfonamide, was obtained.

Melting point: 122-124.

Colorless flaky crystals.

Analysis: Calculated for C H O N S: N, 6.28%.

Found: N, 6.32%.

The advantageous effect of the compounds according to the presentinvention may be illustrated by the following examples:

EXAMPLE 11 4-acetylaminonaphthalene l-sulfonlauroylamide, when caused toact in a tube with the Nakayama strain of the Japanese encephalitisviruses of 10- (100 LD concentration at 22, restrains the virusinfection.

EXAMPLE l2 4-acetylaminonaphthalene-l-sulfonlauroylamide, whenadministered in an amount of 75 mg./kg. into veins of mice which hadbeen i-ntranasally infected with the Nak-ayama strain of the Japaneseencephalitis viruses, showed approximately 0.5-0.2 order increase in LDin comparison with LD of untreated mice group.

EXAMPLE 13 4-acetylaminonaphthalene-l-sulfonlauroylamide, whenadministerd to mice at any time between 1 to 120 minutes afterintran-asal infection with the Nakayama strain of the Japaneseencephalitis viruses, showed the same eifect as in Example 12 by asingle administration.

EXAMPLE 14 According to the report of Komagome Hospital of Tokyo where5%5.0 cc. injection liquid of4-acetylaminonaphthalened-sulfonlau.roylamide was intravenouslyadministered to seriously ill patients with Japanese encephalitis, fortwo days at a rate of 1 to 2 times per day, the death rate was 36%,showing a remarkable decrease in death rate, and the patients recoveredfree from serious results. During the year of 1953, the number ofencephalitis patients throughout the prefecture of Tokyo except those inthe hospital utilizing the present compound, was 194 persons of which 55persons died showing a death rate of 28.3%, while the number of patientsin Komagome Hospital of Tokyo where the present compound was utilized,was 37 persons of which 6 persons died, showing a death rate of 16.2%.

V 10. EXAMPLE 16 4-acetylamino-1-naphthalenesulfonlauroylamide, whencaused to act at 22 on virus of the Lausing Strain of Poliomyelitisvirus of 10- (15 ID concentration, restrains the infecting effect of theviruses at 0.01% concentration.

EXAMPLE 17 N dodecanoyl-4 acetylaminonaphthalenesrulfonamide wasexamined as to its antiviral effect on barnyard fowls suffering fromNewcastle virus, which were found in Osaka district, Japan, in March1954.

(1) 12 adult fowls in critical condition were divided into a treatedgroup and an untreated group. Each fowl of the treated group wassubjected to the following treatment, viz., a dose of 1 cc./kg. of thedrug solution (5 mg./cc.), i.e. 5 mg./kg., was intravenously orsubcutaneously injected for ten days, once daily. The symptoms of thedisease and the survival ratio were observed for another 20 days. Allthe fowls of the treated group recovered with a survival ratio of 6/ 6,while all the fowls of the untreated group died with a survival ratio of0/6. From the above it is evident that the curative effect of the drugis surprisingly high.

(2) 400 young fowls living in a hen house of about 30 square meters areawere found to be suffering from Newcastle disease, and when of them haddied, the drug was first employed. Dumplings were prepared from mixedpowders of the drug and bait, one dumpling including about 25 mg. of thedrug. After oral administration of the dumplings thrice a day for 7days, the symp toms of disease were observed for another 20 days. Onlyone fowl died, while all other fowls recovered, or showed no symptom ofdisease.

The present application is a division of copending application SerialNo. 437,582, filed June 17, 1954, now abandoned.

What is claimed is:

1. A compound which corresponds to the formula NHCOR SO2NHCOR NHCOCH:

wherein x is an integer from 10 to 16 inclusive.

3. N -dodecanoy1 4 acetaminonaphthalenesulfonamide represented by theformula NHCOOHa OzNHCO(CH2)uoCHa 4. N -tetradecanoyl 4acetaminonaphthalenesulfonamide represented by the formula NHCOCH:

6. N -oetadecan0y1. 4 acetaminonaphthalenesulfonv 5. N -hexadecanoy1 4acetaminonaphthalenesulfonamide represented by the formula amiderepresented by the formula NBC 0 OH; NHCOCH;

SOaNHCOMHaMCH: OQNHCO(CHI)16CH$ References Cited in the file of thispatent UNITED STATES PATENTS 2,323,651 Dohrn July 6, 1943 2,394,307 Henrich Feb. 6, 1946 2,411,495 Dohm NOV. 19, 1946

1. A COMPOUND WHICH CORRESPONDS TO THE FORMULA